The research deals with the regulation of neuronal excitability, with a particular emphasis on elucidating the mechanism(s) by which the postsynaptic GABAA receptor may be modified by vasoactive intestinal polypeptide (VIP) in the retina and by norepinephrine (NE) in the cerebellum. We propose a model for how two neurotransmitters working through different receptors may interact synergistically and outline a series of experiments to test it at several key steps along the heteroreceptor cross-talk pathway. In the first portion of the proposal, patch clamp electrophysiological techniques will be combined with focal application of drugs onto neurons acutely dissociated from the rat retina and cerebellum to: 1) investigate the general features of the modulatory phenomenon observed with VIP and NE in retinal bipolar cells ganglion cells and cerebellar Purkinje cells and to 2) determine whether the adenylate cyclase system and cyclic AMP-dependent protein kinase function as intracellular mediators of the modulatory phenomenon observed with VIP and NE. As these studies are progressing, we will also develop the techniques for patch clamp recording in the isolated retina so that, in the latter part of the proposal, we can carry our studies in isolated cells to examine synaptic modulation in the intact neural circuit. To this end, we will 3) investigate the influence of VIP on GABA-mediated physiological parameter(s) in the intact retina. In proposing these aims, we will test the major hypothesis that certain transmitters (e.g., VIP or NE), acting through intracellular transduction mechanisms, can modulate the responsiveness of the target neuron to transmitters which activate ligand-gated ion channels (e.g., the GABAA receptor). Our contention is that, aside from direct excitation or inhibition, such a "heteroreceptor cross-talk" represents an important mode of neurotransmission. To the neuron, the neuromodulators exert a "priming" effect on the state of postsynaptic excitability and thus serves as a bias-adjusting system. Within the context of an operating neuronal circuit, the net result would be an alteration in the gating or efficacy of synaptic transmission.